How the Naked Mole Rat Escapes Inflammatory Pain

Summary: Findings from a study of naked mole rats could be important for helping develop pain therapies for humans.

Source: MDC.

In injuries and inflammation, naked mole-rats do not develop normal hypersensitivity to temperature stimuli. This is due to a tiny change in a receptor molecule on cells called TrkA, as a research team from the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) has now discovered. The work, which appears in the journal Cell Reports, may be important for pain therapy in humans.

When an animal suffers an injury or inflammation, nearby tissue usually becomes highly sensitive to pain. Skin becomes red and puffy, for example, and is hypersensitive to heat. This condition, called “thermal hyperalgesia,” acts as a warning that helps animals avoid further injuries.

The only known animals unable to feel thermal hyperalgesia are naked mole-rats, rodents which live in extremely harsh conditions in underground tunnels. MDC researchers Dr. Damir Omerbasic and Dr. Ewan St. J. Smith from Prof. Gary Lewin’s lab now found out the reasons and presented their work in the latest issue of the journal Cell Reports.

Hyperalgesia is mediated by the signaling molecule Nerve Growth Factor (NGF), which is also responsible for the growth of new nerves, especially during embryonic development. Hyperalgesia occurs when inflamed or injured tissue releases NGF molecules which subsequently bind to protein molecules on the surfaces of specialized, pain-sensing nerve cells. These surface proteins are called TrkA receptors, and when they are stimulated by NGF they relay a signal into the nerve cell. This causes other proteins to interact with the receptor, starting a cascade of biochemical signals which ultimately makes the cell oversensitive to thermal stimuli.

TrkA receptors evolved in an ancient animal and have been passed down to all its descendants. TrkA is so important that it has been protected from most evolutionary change.

When the researchers compared the receptor of naked mole-rats to TrkA receptors in other mammals, they found minute differences in a region of the molecule that projects into the cell interior. This region triggers the biochemical signaling cascade and is virtually identical in all mammals.

In naked mole-rats, the differences in this portion of the receptor alter a few of the protein’s building blocks and severely diminishes the signal-relaying action of the TrkA receptor. The researchers found that it took ten times the amount of NGF compared to TrkA receptors from other animals to trigger the signaling cascade, explaining why naked mole-rats are almost completely insensitive to thermal hyperalgesia.

NGF has another important function: it stimulates the growth and maintenance of nerves as the nervous system develops in the embryo. That’s why defects of the TrkA receptor in other mammals often lead to a degeneration of the nervous system during embryonic development. “The nervous system of the naked mole-rat can develop normally because while the function of its TrkA receptors is lowered, it is not completely abolished,” principal investigator Gary Lewin explains. “Evolution has selected a version of the molecule that can send just enough signal to build a proper nervous system, but not enough to make cells hypersensitive to pain.”

The difference surely makes life more bearable for the rodents, which live underground in densely packed colonies. Injuries and inflammations are common, and under the same conditions other mammals would suffer intense, continual pain.

That’s a daily experience for many people who suffer from chronic pain. In many cases the problem also involves NGF and TrkA; treatments that block the binding of these two molecules have had very positive effects in clinical trials. It’s another example, Gary says, of how basic research – even when it starts in a very unusual animal – could pave the way toward new human therapies.

ABOUT THIS PAIN RESEARCH ARTICLE

Damir Omerbasic and Ewan St. J. Smith contributed equally to this work. This study was funded by the European Research Council (ERC) and the Alexander von Humboldt foundation.

Hypofunctional TrkA Accounts for the Absence of Pain Sensitization in the African Naked Mole-Rat

Highlights
•TRPV1 ion channels in naked mole-rat nociceptors are not sensitized by NGF
•Naked mole-rat TRPV1 channels are sensitized by NGF in mouse nociceptors
•NGF activation of naked mole-rat TrkA receptors does not sensitize TRPV1
•One to three amino acids in the naked mole-rat TrkA receptors may render it hypofunctional

Summary
The naked mole-rat is a subterranean rodent lacking several pain behaviors found in humans, rats, and mice. For example, nerve growth factor (NGF), an important mediator of pain sensitization, fails to produce thermal hyperalgesia in naked mole-rats. The sensitization of capsaicin-sensitive TRPV1 ion channels is necessary for NGF-induced hyperalgesia, but naked mole-rats have fully functional TRPV1 channels. We show that exposing isolated naked mole-rat nociceptors to NGF does not sensitize TRPV1. However, the naked mole-rat NGF receptor TrkA displays a reduced ability to engage signal transduction pathways that sensitize TRPV1. Between one- and three-amino-acid substitutions in the kinase domain of the naked mole-rat TrkA are sufficient to render the receptor hypofunctional, and this is associated with the absence of heat hyperalgesia. Our data suggest that evolution has selected for a TrkA variant that abolishes a robust nociceptive behavior in this species but is still compatible with species fitness.